Leukotriene is derived from arachidonic acid by a lipoxygenase pathway, e.g., leukotriene C4 (LTC4) is synthesized from arachidonic acid by the actions of 5-lipoxygenase and LTC4 synthase. LTC4 has long been recognized as a potent mediator of inflammation involved in diseases such as asthma, cystic fibrosis, acute/chronic bronchitis, gout, rheumatic arthritis, arthritis, allergic rhinitis, skin disorder such as psoriasis, and inflammatory bowel disease. Further, leukotriene is known to be related to various cardiopulmonary diseases including sepsis, cardiac myoischemia, cardiac anaphylaxis, cerebrovascular convulsion and ischemia. Accordingly, a compound capable of selectively suppressing 5-lipoxygenase can be effectively used in treating the above diseases.
There have been reported various compounds suppressing 5-lipoxygenase, e.g., compounds having a hydroxyurea, hydroxamate, aryl alcohol or carboxylic acid Moiety. However, these compounds generally suffer from the multiple problems of toxicity such as formation of methemoglobin and poor bioavailability.
Accordingly, there has been a need to develop a drug capable of suppressing leukotriene-related diseases such as asthma and inflammation diseases by effectively inhibiting 5-lipoxygenase. The present inventors have found that benzoxazole derivatives are effective 5-lipoxygenase inhibitors.
Benzoxazole moieties, which are known to act as antibiotics, antitumors and fluorescent whitening agents, have been synthesized by a number of methods. For instance, Anitha Hari et al. reported a method for synthesizing benzoxazole derivatives using 2-aminophenol and an aldehyde as starting materials (J. Org. Chem. 66 pp.991-996(2001)). Further, for the cyclization of thiourea, an intermediate of benzoxazole derivative, Haruo Ogura et al. used nickel peroxide as an oxidizing agent (J. Soc. Chem. Lett. pp.1291 -1294(1986)), while Hae Sung Chang et al. employed potassium superoxide (Chem. Pharm. Bull 29(6) pp.1518-1524(1981)). However, these methods suffer from the problem of vigorous reaction conditions due to the use of the oxidizing agents.
Accordingly, it is desirable to develop a preparation method thereof which can be carried out in mild conditions.